1. THE MADAGASCAR INTERNATIONAL COOPERATIVE BIODIVERSITY GROUP: BACKGROUND AND HISTORY David Kingston Department of Chemistry Virginia Polytechnic Institute & State University Web: www.kingston.chem.vt.eduwww.kingston.chem.vt.edu

2. Natural Products as Drugs and Drug Leads nWHO estimates that ~80% of the world’s population use traditional medicine. nBetween 1983 and 1994 41% of new approved drugs had natural products as their source. David J. Newman, et al. Nat. Prod. Rep., 2000, 17, 215-234 Gordon M. Cragg, et al. J. Nat. Prod., 1997, 60, 52-60 6% 26% 9% 59% n Natural Product Drugs n Modified Natural Product Drugs n Synthetic Drugs Based on Natural Product Models n Synthetic Drugs

3. MORE REASONS FOR FAITH IN NATURAL PRODUCTS 61% of all the new drugs introduced Worldwide during 1981-2002 can be traced to or were inspired by Natural Products. Newman, Cragg, Snader 2003 J Nat Prod 66:1022 Synthetic Compound from combinatorial chemistry Natural Products Drugs Feher and Schmidt 2003 J Chem Inf Comput Sci 43:218 Chiral ctr = 0.4 Chiral ctr = 6.2 Chiral ctr = 2.3 NP are more diverse than synthetics

4. SOME IMPORTANT ANTICANCER NATURAL PRODUCTS TAXOL, from Taxus brevifolia ■Treatment for ovarian and breast cancer ■Also used in stents to prevent restenosis ■Major drug, with sales of over one billion dollars/year

5. WHY NATURAL PRODUCTS? nNATURAL PRODUCTS CAN FORM THE BASIS OF NEW COMPOUND LIBRARIES R. Breinbauer et al, Angew. Chem. Int. Ed. 2002, 41, 2878 nEXAMPLE: THE HALICHONDRINS M. J. Yu 224th ACS National Meeting, Boston, MA, August 21, 2001, Abstract MEDI 238.

6. DRUG DISCOVERY THROUGH NATURAL PRODUCTS nCOLLECT LARGE NUMBERS OF PLANT, MARINE, OR MICROBIAL SPECIES nPREPARE EXTRACTS AND TEST IN RELEVANT BIOASSAY SYSTEMS nRECOLLECT OR REFERMENT ACTIVE SPECIES AND ISOLATE ACTIVE COMPOUNDS BY A BIOASSAY-DIRECTED FRACTIONATION nDETERMINE STRUCTURES OF BIOACTIVE COMPOUNDS nCARRY OUT ADDITIONAL BIOLOGICAL TESTING

7. THE PROBLEM OF BIODIVERSITY LOSS nDRUG DISCOVERY REQUIRES RANDOM SCREENING OF THOUSANDS OF SPECIES “YOU HAVE TO KISS A LOT OF FROGS TO FIND A PRINCE” nTROPICAL RAINFORESTS COVER ONLY 8% OF THE EARTH’S SURFACE BUT HOLD 50% OF ITS PLANTS nTROPICAL FORESTS ARE DISAPPEARING FAST; DOWN FROM 16% OF EARTH’S LAND SURFACE IN 1950 TO LESS THAN 8% TODAY nTROPICAL REEFS ARE ALSO UNDER THREAT nLOSS OF RAINFOREST MEANS THE POTENTIAL LOSS OF CURES FOR CANCER, AIDS, ETC.

8. Brazil Vegetation 1960

9. Brazil Brazil Vegetation 1988

10. THE MADAGASCAR ICBG APPROACH TO BIODIVERSITY CONSERVATION CARRY OUT BIOPROSPECTING WITH FULL INFORMED CONSENT OF ALL PARTIES PARTNER WITH PHARMACEUTICAL AND AGROCHEMICAL COMPANIES SINCE BIODIVERSITY LOSS IS CLOSELY ASSOCIATED WITH POVERTY, COMBINE BIOPROSPECTING WITH ECONOMIC DEVELOPMENT ACTIVITIES COMMIT TO RETURN ANY ROYALTY PAYMENTS IN PART TO THE HOST COUNTRY IN COMPENSATION FOR USE OF ITS BIODIVERSITY

11. HOW AND WHERE TO DO THIS? n1992 NATIONAL INSTITUTES OF HEALTH INVITED SCIENTISTS TO COMPETE FOR FUNDS TO DO DRUG DISCOVERY AND BIODIVERSITY CONSERVATION n1993-1998 VIRGINIA TECH PROPOSAL FUNDED TO DO WORK IN SURINAME n1998-2003 RENEWAL PROPOSAL FUNDED TO DO WORK IN SURINAME AND MADAGASCAR n2003-2008 THIRD ROUND OF FUNDING AWARDED FOR WORK IN MADAGASCAR

12. MADAGASCAR GROUP STRUCTURE  VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY nCENTRAL OPERATIONS OFFICE  MISSOURI BOTANICAL GARDEN nBOTANICAL COLLECTIONS, BIODIVERSITY SURVEY  CONSERVATION INTERNATIONAL nECONOMIC DEVELOPMENT, BIODIVERSITY CONSERVATION CENTRE NATIONAL D’APPLICATION ET DES RECHERCHES PHARMACEUTIQUES nPLANT EXTRACTS, ANTIMALARIAL FRACTIONATION CENTRE NATIONAL DE RECHERCHES SUR L’ENVIRONNEMENT nMARINE COLLECTION, MICROBIAL ISOLATIONS EISAI RESEARCH INSTITUTE nBIOASSAY, DRUG DISCOVERY AND DEVELOPMENT  DOW AGROSCIENCES nAGROCHEMICAL DISCOVERY AND DEVELOPMENT  VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY nBIOASSAY AND ANTICANCER DRUG DISCOVERY

13. GOALS OF THE MADAGASCAR ICBG PROGRAM TO INTEGRATE THE PROCESS OF DRUG AND AGROCHEMICAL DISCOVERY FROM NATURAL PRODUCTS WITH CONSERVATION OF BIODIVERSITY AND SUSTAINABLE ECONOMIC DEVELOPMENT, WHILE PROVIDING FINANCIAL BENEFITS TO MADAGASCAR AND ITS PEOPLE

14. MADAGASCAR WHY MADAGASCAR? nMadagascar is a prime source of biodiversity. n Madagascar is one of the highest priority “Biodiversity Hotspots” nHome to 25% of the plant species in the African region nApproximately 80% of species are endemic nGreat ecosystem diversity nWork is urgent, since much of the country has been deforested

15. SCIENTIFIC DEVELOPMENT IN MADAGASCAR nLaboratories at CNARP have been equipped to prepare plant extracts nLaboratories at CNARP have been equipped and personnel trained to carry out antimalarial bioassays nFacilities at CNRO (Nosy be) are being equipped to carry out marine collections nPersonnel at CNRE will be trained in microbial isolations nData handling infrastructure has been expanded

16. ECONOMIC DEVELOPMENT IN MADAGASCAR nSMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS BEE KEEPING ECOTOURISM INITIATIVE IMPROVED CROPS

17. ECONOMIC DEVELOPMENT IN MADAGASCAR nSMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS BEE KEEPING ECOTOURISM INITIATIVE IMPROVED CROPS nINFRASTRUCTURE IMPROVEMENTS USING UPFRONT COMPENSATION FUNDS IN THE SAME VILLAGES AGRICULTURAL WAREHOUSE RENOVATION OF A PRIMARY SCHOOL CONSTRUCTION OF A FOOTBRIDGE